Niki Christou

Hallmarks in colorectal cancer: Angiogenesis and cancer stem-like cells

Carcinogenesis is a multistep process that requires the accumulation of various genetic and epigenetic aberrations to drive the progressive malignant transformation of normal human cells. Two major hallmarks of carcinogenesis that have been described are angiogenesis and the stem cell characteristic of limitless replicative potential. These properties have been targeted over the past decade in the development of therapeutic treatments for colorectal cancer (CRC), one of the most commonly diagnosed and lethal cancers worldwide. The treatment of solid tumor cancers such as CRC has been challenging due to the heterogeneity of the tumor itself and the chemoresistance of the malignant cells. Furthermore, the same microenvironment that maintains the pool of intestinal stem cells that contribute to the continuous renewal of the intestinal epithelia also provides the necessary conditions for proliferative growth of cancer stem-like cells. These cancer stem-like cells are responsible for the resistance to therapy and cancer recurrence, though they represent less than 2.5% of the tumor mass. The stromal environment surrounding the tumor cells, referred to as the tumor niche, also supports angiogenesis, which supplies the oxygen and nutrients needed for tumor development. Anti-angiogenic therapy, such as with bevacizumab, a monoclonal antibody against vascular-endothelial growth factor, significantly prolongs the survival of metastatic CRC patients. However, such treatments are not completely curative, and a large proportion of patient tumors retain chemoresistance or show recurrence. This article reviews the current knowledge regarding the molecular phenotype of CRC cancer cells, as well as discusses the mechanisms contributing to their maintenance. Future personalized therapeutic approaches that are based on the interaction of the carcinogenic hallmarks, namely angiogenic and proliferative attributes, could improve survival and decrease adverse effects induced by unnecessary chemotherapy.

Is the 2-cm size cutoff relevant for small nonfunctioning pancreatic neuroendocrine tumors: A French multicenter study.

BACKGROUND Nonfunctioning pancreatic neuroendocrine tumors (NF-PNETs) are often discovered at a small size. No clear consensus exists on the management of NF-PNETs ≤ 2 cm. The aim of our study was to determine the prognostic value of indicators of malignancy in sporadic NF-PNETs ≤ 2 cm. METHODS Eighty patients were evaluated retrospectively in 7 French University Hospital Centers. Patients were managed by operative resection (operative group [OG]) or observational follow-up (non-OG [NOG]). Pathologic characteristics and outcomes were analyzed. RESULTS Sixty-six patients (58% women) were in the OG (mean age, 59 years; 95% CI, 56.0-62.3; mean tumor size, 1.6 cm; 95% CI, 1.5-1.7); 14 (72% women, n = 10) were in the NOG (mean age, 63 years; 95% CI, 56-70; mean tumor size, 1.4 cm; 95% CI, 1.0-1.7). All PNETs were ranked using the European Neuroendocrine Tumor Society grading system. Fifteen patients (19%) had malignant tumors defined by node or liver metastasis (synchronous or metachronous). The median disease-free survival was different between malignant and nonmalignant PNETs, respectively: 16 (range, 4-72) versus 30 months (range, 1-156; P = .03). On a receiver operating characteristic (ROC) curve, tumor size had a significant impact on malignancy (area under the curve [AUC], 0.75; P = .03), but not Ki-67 (AUC, 0.59; P = .31). A tumor size cutoff was found on the ROC curve at 1.7 cm (odd ratio, 10.8; 95% CI; 2.2-53.2; P = .003) with a sensitivity of 92% and a specificity of 75% to predict malignancy. CONCLUSION Based on our retrospective study, the cutoff of 2 cm of malignancy used for small NF-PNETs could be decreased to 1.7 cm to select patients more accurately.

E‑cadherin: A potential biomarker of colorectal cancer prognosis (Review)

Colorectal cancer (CRC) is a common and lethal disease. It is the third most common type of cancer in the world, behind lung and breast cancer, with almost 1.4 million new cases diagnosed in 2012. The risk of developing CRC is influenced by environmental and genetic factors. Adenocarcinomas comprise the vast majority (98%) of CRCs. A patients likelihood of survival is associated with the tumor stage at the time of diagnosis. With regular screening, CRC can be identified early, when treatment is the most effective. However, CRC is typically asymptomatic until the advanced stages. The combination of the absence of symptoms and current screening methodology results in a significant number of patients being diagnosed in advanced stages. The purpose of the present review is to discuss and summarize the biomarkers linked to CRC progression, particularly the controversial E-cadherin, which is a calcium-dependent cell-cell adhesion molecule involved in the mesenchymal-epithelial transition.

New ex-ovo colorectal-cancer models from different SdFFF-sorted tumor-initiating cells.

Despite effective treatments, relapse of colorectal cancer (CRC) is frequent, in part caused by the existence of tumor-initiating cells (TICs). Different subtypes of TICs, quiescent and activated, coexist in tumors, defining the tumor aggressiveness and therapeutic response. These subtypes have been sorted by hyperlayer sedimentation field-flow fractionation (SdFFF) from WiDr and HCT116 cell lines. On the basis of a new strategy, including TIC SdFFF sorting, 3D Matrigel amplification, and grafting of corresponding TIC colonies on the chick chorioallantoic membrane (CAM), specific tumor matrices could be obtained. If tumors had similar architectural structure with vascularization by the host system, they had different proliferative indices in agreement with their initial quiescent or activated state. Protein analysis also revealed that tumors obtained from a population enriched for “activated” TICs lost “stemness” properties and became invasive. In contrast, tumors obtained from a population enriched for “quiescent” TICs kept their stemness properties and seemed to be less proliferative and invasive. Then, it was possible to produce different kinds of tumor which could be used as selective supports to study carcinogenesis and therapy sensitivity.

Long-term voice quality outcomes after total thyroidectomy: a prospective multicenter study

Background. Postthyroidectomy voice disorders can occur without any recurrent laryngeal nerve injury, and probably are the most frequent complication after thyroidectomy. We report the long‐term voice quality outcomes after total thyroidectomy without vocal cord palsy using a simple self‐assessment tool: the voice handicap index self‐questionnaire. Methods. This observational prospective multicenter study included 203 patients from the “ThyrQoL” study (ClinicalTrial NCT02167529), who underwent total thyroidectomy between October 2014 and August 2015 in 3 French Hospitals (Nantes, La Roche‐sur‐Yon, and Limoges). Exclusion criteria included confirmed malignant disease, age <18 years, and preoperative voice troubles with confirmed vocal cord palsy. Direct flexible laryngoscopy was performed after surgery. Nineteen patients with a postoperative vocal cord palsy were excluded from analysis. Results. One hundred and seventy‐six patients with no vocal cord palsy were analyzed. Voice handicap index scores were significantly altered on postoperative month 2 compared with preoperative values (7.02 ± 11.56 vs 14.41 ± 19.44; P < .0001). Voice handicap index scores were not significantly different on postoperative month 6 compared with preoperative values (7.02 ± 11.56 vs 7.61 ± 14.02; P = .381). Thirty‐six patients (20.5%) described significant voice impairment 2 months after total thyroidectomy. Nine patients (5.7%) still experienced significant discomfort at 6 months. Conclusion. Twenty percent of patients had initial voice impairment at 2 months postthyroidectomy, with a progressive recovery to preoperative levels at 6 months with <6% with persistent voice complaints.

Stepwise management of hepatocellular carcinoma associated with Abernethy syndrome

Patients with congenital agenesis of the portal vein may develop hepatocellular tumors due to enhanced arterial blood flow. These tumors may be benign (FNH, adenomas) or malignant (hepatoblastoma, HCC). Liver resection can be proposed, and preoperative arterial embolization may decrease blood loss during surgery. Liver transplantation with PV reconstruction is also an option.

Advanced age does not increase morbidity after total thyroidectomy. Result of a prospective study

BACKGROUND It is well known that total thyroidectomy is feasible on elderly patients but is linked to complications because of their underlying comorbidities. In this study we analyzed the specific risks linked to surgery, hypoparathyroidism and recurrent nerve palsy. METHODS materials-methods:Prospective, multicentre trial conducted at 13 hospital sites. The primary endpoint was the percentage of patients with postoperative hypocalcaemia (albumin-corrected serum calcium level <2 mmol/L at day 2). Secondary endpoints included recurrent nerve palsy rate at day 2, the percentage of patients with hypocalcaemia (serum calcium level <2 mmol/L) and recurrent nerve palsy at month 6, operating durations and postoperative pain. Patients were separated in two groups: <70 years and ≥70 years old. RESULTS In total, 1329 patients who underwent total thyroidectomy were included (median age 51.17 years [18.10; 80.90], 80% women, and hyperthyroidism in 20%, 101 ≥ 70 years old). Rates of hypocalcaemia at day 2 and month 6 were 20.02% and 1.98% respectively. Nasofibroscopy showed postoperative abnormal vocal cord motility in 9.92% cases (hypo-motility 5.76% - immobility 4.16%) and 0.95% at month 6 (hypo-motility 0.48%, immobility 0.48%). Patients ≥70 years had a lower (but non-significant) postoperative and definitive hypocalcaemia rate than patients < 70 years: 14.85% vs 20.44% at day 2 (p = 0.1773) and 0% vs 2.15% at month 6 respectively (p = 0.2557). Abnormal vocal cord motility rate was 12.00% in patients ≥70 years vs 9.75% in patients <70 years at day 2 (p = 0.4702), and 2.06% in patients ≥70 years vs 0.86% at month 6 (p = 0.2340). CONCLUSIONS Total thyroidectomy in patients ≥70 years is feasible and safe. Age does not increase the morbidity. The study is registered with ClinicalTrials.gov number NCT01551914.